EP0814793A1 - Aerosolzusammensetzungen mit prilocaine und fluorokohlenwasserstoff - Google Patents

Aerosolzusammensetzungen mit prilocaine und fluorokohlenwasserstoff

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Publication number
EP0814793A1
EP0814793A1 EP96902844A EP96902844A EP0814793A1 EP 0814793 A1 EP0814793 A1 EP 0814793A1 EP 96902844 A EP96902844 A EP 96902844A EP 96902844 A EP96902844 A EP 96902844A EP 0814793 A1 EP0814793 A1 EP 0814793A1
Authority
EP
European Patent Office
Prior art keywords
prilocaine
hfc
base
group
prilocaine base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP96902844A
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English (en)
French (fr)
Other versions
EP0814793B1 (de
Inventor
Richard A. Henry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Richard A Henry
Original Assignee
HENRY Richard A
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Priority claimed from US08/405,930 external-priority patent/US5593661A/en
Priority claimed from US08/408,877 external-priority patent/US5534242A/en
Application filed by HENRY Richard A filed Critical HENRY Richard A
Publication of EP0814793A1 publication Critical patent/EP0814793A1/de
Application granted granted Critical
Publication of EP0814793B1 publication Critical patent/EP0814793B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention is generally related to aerosol formulations which include hydrofluoride propellants and prilocaine base.
  • Prilocaine is a local anesthetic drug which has the chemical formula:
  • Prilocaine is described in British Patent 839,943 (1960 to Astra) , and takes the form of crystalline needles having a melting point of 37-38°C.
  • the hydrochloride salt having the formula C
  • Local anesthetic drugs block nerve impulses by interfering with the opening of voltage gated sodium channels of excitable membranes, such as neuronal cell membranes. When enough channels are blocked, neuronal conduction is terminated within the anesthetized portion of the particular nerve axon. This mechanism of pain relief is quite different from those used by analgesic agents.
  • the potency of anesthetics in clinical situations depends on both the ability to reach the nerve fibers and their intrinsic blocking activities. Factors such as nerve sheath penetration, vascular absorption, and local tissue binding are all important determinants of functional potency. In addition, volume, pH, and buffering capacity of the injected anesthetic solution are important.
  • Local anesthetics are traditionally injected into the desired site of action by the use of a needle and syringe.
  • Most formulations of local anesthetics are aqueous solutions of the hydrochloride salt forms of the drug in 0.5-2% weight/volume concentrations. These solutions are designed for injection either diffusely into tissue, around nerves, or into the intrathecal or epidural spaces.
  • the delivery of local anesthetic agents to skin wounds remains a problem and is largely still achieved by injection of the aqueous local anesthetic around or into the wound.
  • This treatment mechanism can be disadvantageous because the needle itself causes pain on penetration, and, the volume of anesthetic solution can cause stretching at the site, which also causes pain.
  • preservatives such as parabens, ethyl alcohol, cetylpyridinium chloride, benzalkonium chloride, and the like, which may be used in the aqueous solution can cause stinging at the wound site.
  • a topical formulation of 0.5% tetracaine hydrochloride, epinephrine 1:2000, and 11.8% cocaine hydrochloride, is described in Handbook of Pediatric Emergencies. 1994, Ed. Baldwin, Little, Brown and Company. This formulation is applied by holding a cotton ball soaked in the solution for a period of 10-15 minutes.
  • This treatment scheme and formulation suffers from the slow absorption of the salt form of the local anesthetic which requires that the solution be held in place for long periods of time, the use of cotton balls directly on the wound site, and the requirement of cleaning the wound prior to application of the formulation.
  • the treatment scheme must be supplemented with injection of a local anesthetic formulation.
  • Topical anesthesia requires rapid absorption of drug in order to block nerve conduction.
  • Topically applied gels and fluids have not proven successful in many environments. For example, intraurethrally delivered lidocaine gel was shown to be no more effective than plain lubricant jelly during cystoscopy (see. Stein et al.. Journal of Urology, June 1994, Vol. 151, pages 1518-1521).
  • Lidocaine has been delivered in aerosol form to the mucous membranes of the airway using nebulized aqueous preparations of the lidocaine hydrochloride salt and using metered dose inhaler (MDI) formulations with chlorofluorocarbon (CFC) propellants and solubilizing and/or dispersing agents.
  • MDI metered dose inhaler
  • CFC chlorofluorocarbon
  • these formulations suffer from large droplet formation which prevents satisfactory inhalable or indirect delivery to the upper airway, including the larynx and trachea.
  • the requirement of organic solvents and adjuvants in the aerosol formulations limits the concentration of the active medicament, and thus limits the dispensable dose.
  • Chlorofluorocarbon (CFC) propellants have been widely used in aerosol formulations; however, CFC propellants are being phased out under international treaties due to their possible adverse impact on the ozone layer.
  • Hydrofluorocarbon (HFC) propellants have been investigated extensively as substitutes for CFCs.
  • prilocaine in base form has been found to be soluble in the HFC propellants 1,1,1,2- tetrafluoroethane and 1, 1,1,2, 3,3, 3-heptafluoropropane.
  • Prilocaine is soluble when combined with the HFC propellant in liquid form, but is not soluble when combined with the HFC propellant in its crystalline form.
  • the combination of prilocaine base in liquid form and HFC propellant forms a stable liquid solution having an oily consistency.
  • prilocaine base in liquid form When prilocaine base in liquid form is mixed with the HFC propellant it is thought to form a 1:1 molecular ionic complex that keeps the prilocaine in solution and alters the solubility of this complexed mixture such that it is completely miscible or soluble in prilocaine.
  • the prilocaine complexed HFC propellant has altered physical characteristics with improved solubility, improved suspension characteristics, a low vapor pressure and higher viscosity.
  • the association or complex between prilocaine and HFC propellants is disrupted by the presence of water or ethanol resulting in the release of the HFC propellant.
  • Prilocaine liquid can be combined with other medicaments, and particularly other anesthetics, and serve as a solubilizing agent by improving the solubility characteristics of the HFC propellant such that the added local anesthetic forms a stable solution in the prilocaine/HFC solution complex.
  • the oily character of the prilocaine liquid/HFC complex may serve as a valve lubricating aid when dispensing the aerosol formulation from an MDI; thereby, overcoming or obviating the conventional formulations which need additional valve lubricants.
  • the prilocaine liquid/HFC complex also allows the creation of stable suspensions of certain particulate medicaments (e.g., beta-agonists such as albuterol, etc.) .
  • the liquid character of the prilocaine/HFC complex may be advantageous in topical treatment methodologies since the prilocaine can be sprayed onto a site to coat the site with a liquid, as opposed to a fine powder, which will be more rapidly absorbed due to the liquid character of the prilocaine, the fact that the prilocaine is present as a lipid- soluble base, and the rapid departure of the complexed HFC propellant from the interaction of the complex with water on the membrane and skin surfaces of the patient.
  • Liquid prilocaine base can be made by suspending prilocaine hydrochloride in ethyl acetate and washing with a suitable aqueous base, such as sodium bicarbonate, until all the solid is consumed.
  • a suitable aqueous base such as sodium bicarbonate
  • the ethyl acetate can be removed using standard rotary evaporation or other procedures.
  • the prilocaine base residue is then dissolved in a lower boiling point solvent, such as dichloromethane, to remove the ethyl acetate by azeotropic distillation.
  • the dichloromethane is then evaporated off using a rotary evaporator, and the prilocaine base is dried under high vacuum.
  • the prilocaine base obtained by the above procedure was a liquid at room temperature, but was easily converted to its usual crystalline needle form by cooling or by the addition of crystal seeds to the liquid.
  • prilocaine is ordinarily a solid at room temperature which has the form of crystalline needles that melt at 38°C.
  • the processing conditions used formed a liquid prilocaine base below its normal melting point. This is not an unusual occurrence where a low melting point solid is found to remain in liquid form below its melting point; however, this property in prilocaine base has been heretofore unknown. Further cooling or the addition of crystal seeds crystallizes these substances and they remain in solid form up to their predicted melting point.
  • a reference standard prilocaine base sample obtained from the Astra Pharmaceutical Company of Sweden was used to verify the nature and purity of the liquid prilocaine base as described above. It was confirmed using thin layer chromatography on silica gel, infra-red (IR) spectrometry, and nuclear magnetic resonance (NMR) imaging that the liquid prilocaine base was the same as the standard prilocaine base. It has been discovered that the liquid prilocaine base can be readily solubilized or absorbed into HFC propellants 1, 1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3- heptafluoropropane. The combination of liquid prilocaine base and the HFC propellant forms a stable oily liquid.
  • prilocaine base in micro rod crystal form is soluble in HFC propellants.
  • Micro rods of prilocaine base may be obtained using precipitation and filtering from a super ⁇ saturated solution.
  • the Reference Standard Sample of prilocaine base from Astra Pharmaceuticals was provided in micro rod crystal form. The micro rods are identical to the crystalline needles of prilocaine base chemically, but not physically.
  • prilocaine base be used in liquid form or micro-rod form when making aerosol formulations with HFC propellants.
  • Combining liquid or micro-rod prilocaine base with HFC propellants produces a stable complex or association that has the form of an oily liquid solution which can be used in MDIs or other formulations.
  • the solution is ideal for topical delivery to a wound site or the like, in that the prilocaine base is applied as a liquid and is absorbed quickly, absorption is enhanced by the prilocaine being present in its lipid soluble base form, and the complexed HFC propellant quickly dissociates from the prilocaine upon contact with water and other contaminants at the site.
  • the rapid absorption allows for quick and effective local anesthesia without causing pain or discomfort on application.
  • the prilocaine base is in liquid form as it is sprayed, it has the utility of forming a thin film coating on any site needing to be anesthetized.
  • sites include the mucous membranes of the airway, gastrointestinal tract and genito-urinary tract, and all wound surfaces where the epidermis is compromised to allow rapid absorption of topical local anesthetic as well as internal organ surfaces exposed during surgical procedures.
  • the oily character of the liquid improves absorption to the applied surface while remaining easy to wash or wipe off.
  • Example 1 describes the formation of the complex of liquid prilocaine base and HFC propellants.
  • Liquid prilocaine base provided as an oily liquid without any crystal seeds, is readily miscible with the hydrofluorocarbon propellants 1,1,1,2-tetrafluoroethane (HFC- 134a) and 1, 1, 1,2,3,3,3-heptafluoropropane (HFC-227).
  • prilocaine base in micro rod crystalline form is readily miscible with the hydrofluorocarbon propellants 1, 1, 1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3- heptafluoropropane (HFC-227) .
  • the combination of the liquid prilocaine base or micro rod prilocaine base and the HFC propellants forms a stable liquid solution.
  • liquid prilocaine was placed in a 4 ounce glass bottle of known weight. The bottle was weighed to determine the weight of liquid prilocaine base. The bottle was then sealed with a continuous valve. HFC-134a was added to the bottle by pressure fill. The bottle was weighed again to determine the weight of HFC-134a added. The bottle was agitated gently to ensure intermingling of the liquid prilocaine base and the HFC. The mixture was found to form a clear and stable solution that did not precipitate out the prilocaine base when left standing or cooled. The valve was opened for short intervals to let out vaporized HFC-l34a gas, and the bottle was weighed intermittently.
  • liquid prilocaine base can be used in cold-filling operations that are ordinarily used in MDI packaging or the like without adverse consequences. Seeding of the 1:1 solution with prilocaine base needle crystals resulted in the prilocaine base crystallizing out of solution over several days.
  • the association of liquid prilocaine base with HFC propellants has been found to allow its use as a solubilizing agent for dissolving and/or dispersing other medicaments within HFC propellants.
  • prilocaine base can be used as a solubilizing aid for other local anesthetics, most of which are not ordinarily soluble in HFC propellants.
  • prilocaine base can be used in HFC propellants in combination with the anesthetics procaine, cocaine, chloroprocaine, tetracaine, mepivacaine, lidocaine, bupivacaine, etidiocaine, ropivacaine, and benzocaine.
  • Prilocaine may be used in the preparation of HFC aerosol formulations that are used in inhalation (nasal and/or oral), and topical delivery (e.g., skin wounds, hollow viscus and body cavity delivery) , and may be used to solubilize, disperse and/or form stable suspensions with other medicaments including, for example, bronchodilators, anti-inflammatories, antitussives, vasoactive drugs, vasoconstrictors, antibiotics, peptides, steroids, enzymes, antihistamines, benzodiazepines, anti-psychotics, sedatives, vitamins, hormones, enzyme and receptor inhibitors and agonists, 5-aminolevulinic acid and similar agents, antiseptics and disinfectants, etc.
  • bronchodilators anti-inflammatories, antitussives, vasoactive drugs, vasoconstrictors, antibiotics, peptides, steroids, enzymes, antihistamines, benzodiazep
  • Example 2 provides the compositions of several different HFC aerosol formulations which have been prepared. It can be seen that prilocaine base can be used at widely varying concentrations and may range from 1-99% by weight of the aerosol formulation. Most preferably, the liquid prilocaine base will constitute 1-60% by weight of the HFC aerosol formulation. The HFC propellant can constitute 1-99% by weight of the aerosol formulation, and most preferably 60% to 95% by weight of the aerosol formulation.
  • Prilocaine base 184.6 mg 56.2% w/w
  • Benzocaine base 12.7 mg 3.8% w/w
  • Formulations 9-10 demonstrate that prilocaine can be used to enhance the solubility of certain medicaments in HFC propellants Formulation 11
  • the three medicament bases were first heated and dissolved together. This formulation produced a stable suspension of the phenylephrine. No signs of crystal growth were observed.
  • Formulation 13 Phenylephrine base 3 g 0.2% w/w

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP96902844A 1995-03-17 1996-03-04 Aerosolzusammensetzungen mit prilocaine und fluorokohlenwasserstoff Expired - Lifetime EP0814793B1 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US435812 1982-10-21
US405930 1995-03-17
US08/405,930 US5593661A (en) 1993-03-29 1995-03-17 Lidocaine aerosol anaesthetic
US08/408,877 US5534242A (en) 1994-05-02 1995-03-24 Lidocaine-vasoconstrictor aerosol preparation
US408877 1995-03-24
US08/435,812 US5589156A (en) 1994-05-02 1995-05-05 Prilocaine and hydrofluourocarbon aerosol preparations
PCT/CA1996/000122 WO1996029066A1 (en) 1995-03-17 1996-03-04 Prilocaine and hydrofluorocarbon aerosol preparations

Publications (2)

Publication Number Publication Date
EP0814793A1 true EP0814793A1 (de) 1998-01-07
EP0814793B1 EP0814793B1 (de) 2003-07-16

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ID=27410659

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96902844A Expired - Lifetime EP0814793B1 (de) 1995-03-17 1996-03-04 Aerosolzusammensetzungen mit prilocaine und fluorokohlenwasserstoff

Country Status (13)

Country Link
US (1) US5589156A (de)
EP (1) EP0814793B1 (de)
JP (1) JP4117707B2 (de)
CN (1) CN1149080C (de)
AT (1) ATE245025T1 (de)
AU (1) AU710600B2 (de)
BR (1) BR9607988A (de)
DE (1) DE69629109T2 (de)
DK (1) DK0814793T3 (de)
ES (1) ES2203676T3 (de)
LU (1) LU92402I2 (de)
PT (1) PT814793E (de)
WO (1) WO1996029066A1 (de)

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EP0814793B1 (de) 2003-07-16
CN1179103A (zh) 1998-04-15
LU92402I2 (fr) 2014-05-19
US5589156A (en) 1996-12-31
MX9707073A (es) 1998-08-30
JPH11502202A (ja) 1999-02-23
ES2203676T3 (es) 2004-04-16
AU4711396A (en) 1996-10-08
DE69629109D1 (de) 2003-08-21
AU710600B2 (en) 1999-09-23
ATE245025T1 (de) 2003-08-15
JP4117707B2 (ja) 2008-07-16
BR9607988A (pt) 1999-11-30
DE69629109T2 (de) 2004-04-15
CN1149080C (zh) 2004-05-12
WO1996029066A1 (en) 1996-09-26
PT814793E (pt) 2003-12-31
DK0814793T3 (da) 2003-12-01

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